Millions of Americans are victims of traumatic brain injury (TBI), making it a serious health challenge. TBI often involves significant axonal injury with attendant neuronal deafferentation and synaptic loss. While the brain has an inherent capacity for synaptic reorganization, this plasticity often fails after TBI, resulting in serious functional deficits. We have examined the role of extracellular matrix (ECM) proteins during reactive synaptogenesis induced by TBI. Certain ECM proteins and their regulatory matrix metalloproteinases (MMPs) appear to influence the extent of recovery achieved after TBI. Our initial studies contrasted ECM/MMP response in a recovering adaptive injury (unilateral entorhinal cortical lesion or UEC) and a non-recovering maladaptive insult (fluid percussion TBI + bilateral entorhinal cortical lesion or TBI+BEC). Two gelatinases (MMPs 2,9), stromelysin-1 (MMP 3) and the membrane bound MT-5 MMP all showed change in expression and function which correlated with different phases of reactive synaptogenesis. ECM shifts in agrin, tenascin, RPTP-2 and N-cadherin occurred during postinjury recovery as well. We also found that aberrant MMP activation was linked with failed plasticity after TBI+BEC. When MMP inhibitors were applied, plasticity was altered either positively or negatively depending upon dosing and complexity of injury. Given these results, we now posit that specific matrix enzyme/substrate pairs mediate different phases of pre and postsynaptic recovery, as well as the subsequent synapse stabilization. By contrasting profiles of these matrix proteins after adaptive UEC and maladaptive TBI+BEC, we will determine if individual protein dysfunction at specific phases of synaptogenesis can account for the extent of recovery achieved. We will test the facilitative role of MMP3/agrin during the axonal sprouting phase of synaptic recovery, tenascin/RPTP-2/2-catenin during the synaptogenic period, and MT-5MMP/N-cadherin at synapse maturation. For each molecule we will document protein/mRNA expression, synaptic distribution and, when applicable, binding interactions. Finally, we will manipulate MMP3, RPTP-2 and MT-5MMP by either pharmacological inhibition or siRNA knockdown and examine recovery using structural and physiological indices of synaptic plasticity. These studies will better define matrix role in TBI-induced synaptic plasticity and provide new treatment strategies. PUBLIC HEALTH RELEVANCE: Common feature of head injury is poor recovery of damaged brain connections. The proposed studies will determine the role of extracellular matrix proteins during this recovery and identify matrix manipulations which would improve recovery.